ArticleEuropean journal of medicinal chemistry2020
Pyrrolo[2,3-d]pyrimidine derivatives as inhibitors of RET: Design, synthesis and biological evaluation.
Article in European journal of medicinal chemistry, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 27 citations in OpenAlex.
- Design and synthesis of novel indolinone Aurora B kinase inhibitors based on fragment-based drug discovery (FBDD).Molecular diversity · 2026Article
- Side Chain Investigation of Imidazopyridazine as a Hinge Binder for Targeting Actionable Mutations of RET Kinase.ACS medicinal chemistry letters · 2024Article
- Pyrazolopyridine-based kinase inhibitors for anti-cancer targeted therapy.RSC medicinal chemistry · 2024Review
- Discovery of 9H-pyrimido[4,5-b]indole derivatives as dual RET/TRKA inhibitors.Bioorganic & medicinal chemistry · 2024Article
- Discovery of N-Trisubstituted Pyrimidine Derivatives as Type I RET and RET Gatekeeper Mutant Inhibitors with a Novel Kinase Binding Pose.Journal of medicinal chemistry · 2022Article
- Discovery of imidazo[1,2-a]pyridine-thiophene derivatives as FLT3 and FLT3 mutants inhibitors for acute myeloid leukemia through structure-based optimization of an NEK2 inhibitor.European journal of medicinal chemistry · 2021Article
- Targeting Rearranged during Transfection in Cancer: A Perspective on Small-Molecule Inhibitors and Their Clinical Development.Journal of medicinal chemistry · 2021Review
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7 authors at 1 institution in 1 country.
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Abstract
Gene fusions and point mutations of RET kinase are crucial for driving thoracic cancers, including thyroid cancer and non-small cell lung cancer. Various scaffolds based on different heterocycles have been synthesized and evaluated as RET inhibitors. In this work, we investigate pyrrolo[2,3-d]pyrimidine derivatives for inhibition of RET-wt, drug resistant mutant RET V804M and RET gene fusion driven cell lines. Several compounds were synthesized and the structure activity relationship was extensively studied to optimize the scaffold. Thieno[2,3-d]pyrimidine, a bioisostere of pyrrolo[2,3-d]pyrimidine, was also explored for the effect on RET inhibition. We identified a lead compound, 59, which shows low nanomolar potency against RET-wt and RET V804M. Further 59 shows growth inhibition of LC-2/ad cells which RET-CCDC6 driven. We also determined that 59 is a type 2 inhibitor of RET and demonstrated its ability to inhibit migration of tumor cells. Based on computational studies, we proposed a binding pose of 59 in RET pocket and have quantified the contributions of individual residues for its binding. Together, 59 is an important lead compound which needs further evaluation in biological studies.
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